This project is one of four being proposed as part of the UCSD Autism Center of Excellence. One major goal[unreadable] of this study is to identify, in postmortem brain tissue, distinct gene expression profiles of autism that can[unreadable] implicate risk genes for this highly heritable disorder. A second major goal is to identify, in circulating blood[unreadable] cells, a validated gene expression profile of autism that can be developed as a diagnostic tool to improve its[unreadable] identification and early treatment. Although autism is recognized as having a substantial genetic component,[unreadable] its biological basis remains unknown. Due to its high heritability, much research has focused on identifying[unreadable] candidate genes that influence the disorder; however, progress has been slow. In part, this may be[unreadable] attributable to the "single-marker" approach adopted in most prior efforts, since the etiologic complexity and[unreadable] heterogeneity of autism-spectrum disorders invariably thwart classification schemes relying on a single[unreadable] dimension to differentiate affected and unaffected children. To move beyond this single-marker approach, a[unreadable] major objective of the proposed project is to validate suspected risk genes for autism (e.g., genes in the[unreadable] apoptosis, neurogenesis, and Drosophila wingless homolog [wnf] pathways), but also to find new candidate[unreadable] genes by observing patterns of expression of the entire human transcriptome in eight distinct brain regions.[unreadable] The lack of etiologic understanding of autism has also precluded the development of biologically based[unreadable] diagnostic strategies. As such, the diagnosis relies solely on observable behaviors emerging during the first[unreadable] years of life. Yet, the advantages of a more efficient biologically based diagnostic tool for autism are[unreadable] numerous, and as such, another major objective of this study is to develop biologically based markers for[unreadable] autism. To accomplish these objectives, we will pursue five specific aims as follows: 1) Identify ubiquitous[unreadable] and region-specific disruptions in brain gene expression in autism; 2) Identify blood-based predictive[unreadable] biomarkers of early-onset autism; 3) Identify blood-based predictive biomarkers of autism treatment[unreadable] response; 4) Prioritize and verify the differential expression of top candidate genes in postmortem brain and[unreadable] peripheral blood; and 5) Integrate the results of this project with other projects within the Center. The[unreadable] attainment of the :specific aims outlined above will serve to validate several groups of risk genes for autism,[unreadable] identify a new set of potential risk genes, and validate peripheral blood-based biomarkers of the disorder, all[unreadable] while determining the specificity of these effects relative to other developmental disorders and to normal[unreadable] development. The identification of risk genes for autism should facilitate the development of novel[unreadable] therapeutics, while the eventual development of a biological marker system for autism would greatly[unreadable] enhance the efficiency of current diagnostic methods, and it likely would facilitate the search for additional[unreadable] etiologic factors in the disorder.